“These findings, taken together with those of a phase 2 study of atezolizumab (which has anti-PD-L1 [programmed death-ligand 1] activity), provide significant data showing that blockade of the PD-1–PD-L1 immune inhibitory pathway can elicit meaningful clinical responses in patients with metastatic urothelial carcinoma”, the researchers comment in The Lancet Oncology.

The phase II single-arm study of nivolumab 3 mg/kg given every 2 weeks included 270 patients in 11 countries, with activity data available for 265 patients with a median follow-up of 7.0 months.

A confirmed objective response was achieved in 19.6% of the participants after a median of 1.87 months, with a complete response in 2% and a partial response in 17%. A further 23% of patients had stable disease, 39% experienced progressive disease and 18% did not have assessable records.

The median duration of response was not reached in the 52 patients with a confirmed response, with treatment ongoing in 77% of these patients at time of the current analysis, write Padmanee Sharma, from the University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

Of note, a confirmed objective response was found in 28.4% of the 81 patients who had tumour PD-L1 expression of 5% or above, 23.8% of the 122 patients with expression of 1% or higher, and 16.1% of the 143 patients with expression below 1%.

“In all treated patients and in all PD-L1 subgroups, the lower bound of the 95% CI [confidence interval] for objective response was greater than 10%, the prespecified threshold below which objective response was not considered an improvement over the historical control of single-drug chemotherapy”, the investigators observe.

Nivolumab showed activity in all other predefined patient subgroups except in those with three Bellmunt risk factors for a poor prognosis; patients with none of these risk factors had a higher objective response rate than those with one, two or three (25 vs 19, 13 and 7%, respectively).

Median progression-free survival was 2.00 months. Median overall survival was 8.74 months in the whole population but this ranged from 11.30 months for patients with PD-L1 expression of 1% or above to 5.95 months with PD-L1 expression below 1%.

Nivolumab-related adverse events occurred in 64% of 270 participants, most commonly fatigue affecting 17% of the patients. Grade 3 events occurred in 18% of patients, with fatigue and diarrhoea both occurring in 2% of patients and rash and asthenia both in 1% of patients. There were no grade 4 events but three treatment-attributed deaths were reported from pneumonitis, acute respiratory failure and cardiovascular failure.

“Most select adverse events resolved and were manageable with immune-modulating drugs”, the authors write. Quality of life scores were stable over treatment and patients’ global health status scores continued to improve up to week 41, they add.

Finally, the researchers looked at tumour gene expression profiles and found a correlation between the 25-gene interferon (IFN)-γ signature and both increasing response to nivolumab and higher PD-L1 expression. Patients with a high IFN-γ signal – most often those with basal 1 subtype tumours – were significantly more likely to respond to nivolumab than patients with a low signal .

In addition, patients with high CXCL9 or CXCL10 expression signature were more likely to respond to nivolumab than those with lower expression of the cytokines and again this was associated with the basal 1 subtype and higher PD-L1 expression.

“Thus, the potential predictive value of interferon-γ signature warrants further study”, the team concludes. “Our findings advance insights into the mechanistic underpinnings of response to immune checkpoint inhibition and understanding of de-novo resistance.”